As tumors are serious diseases that threaten human health, the study of tumor-related genes has always been an important subject of human biology. Breast cancer is a common tumor, which is one of the most malignant tumors for women, and it usually occurs in European and American countries. In China, especially in some developed areas, the incidence of breast cancer rises year by year, and breast cancer has been a serious threat for women's health.
Estrogen receptor α (ERα) is a hormone-dependent nuclear transcription factor; it is expressed in about 70% of breast tumors. The estrogen binds to estrogen receptor, inducing receptor dimerization, and then the receptor is recruited to the estrogen response element in ERα target gene promoter regions. Since ERα plays a major role in the development and progression of breast cancer, the current endocrine therapy of breast cancer is mainly target ERα signaling pathways, including: reducing estrogen levels; antagonizing ERα function; or decreasing ERα expression levels. In these target ERα endocrine therapies, tamoxifen, a selective estrogen receptor modulator, can bind to ERα through competition and suppress the growth of breast cancer, and it has become the predominant endocrine therapy of breast cancer in recent 30 years. However, primary or secondary tamoxifen resistances are important challenges for the treatment of this disease. ERα itself is the most important determinant to determine whether or not breast cancer is sensitive to the endocrine therapy, and the decrease or elimination of ERα expression level often causes resistance to endocrine therapy. Studies have shown that, the decrease of ERα expression level usually is due to post-transcriptional or post-translational regulation in certain breast cancer tumors. For example, Src and AIB 1 can decrease ERα level in hormone dependent manner; however the mechanism of the decrease of ERα level in breast cancer is not fully clear.
CUEDC2 (Gene ID: 79004) is a protein whose function is not clear. Bioinformatics analysis indicates that CUEDC2 contains a CUE domain. It has been reported that CUE domain is a kind of relatively conservative ubiquitin-binding domain and it contains about 40 amino acids. It widely exists in many eukaryotic proteins. CUE domain can bind to ubiquitin monomer and polyubiquitin. Our previous study found that CUEDC2 degrades the progesterone receptor and participates in the breast cancer cell growth regulation (Zhang, P. J., Zhao, J., et al. 2007. CUE domain containing 2 regulates degradation of progesterone receptor through ubiquitin-proteasome. EMBO J 26(7): 1831-1842). Our recent study shows that CUEDC2 binds to IKK complex, recruits GADD34 and PP1, suppresses over-activation of NF-κB signaling pathway, and involves in the regulation of inflammatory response (Li, H. Y., Liu, H., et al. 2008. Deactivation of the kinase IKK by CUEDC2 through recruitment of the phosphatase PP1. Nat Immunol 9(5): 533-541).